1. Field of the Invention
The present invention relates to a new use of a hydantoin derivative, in particular, (2S,4S)-6-fluoro-2′,5′-dioxospiro [chroman-4,4′-imidazolidine]-2-carboxamide, as a pharmaceutical preparation.
2. Description of the Related Art
The number of patients with diabetes mellitus as a life style-related disease is increasing, and in a survey on diabetes mellitus in 2002 conducted by the Ministry of Health, Labor and Welfare, the number of patients with diabetes mellitus in Japan is estimated to be 7.4 millions. In a recent epidemiological study on 913 cases of non-insulin-dependent diabetes mellitus, about 8% (about 600,000 patients) of patients with diabetes mellitus are reported to have maculopathy. It is estimated that as the number of patients with diabetes mellitus increases, the number of patients with diabetic maculopathy also increases.
Diabetic maculopathy, together with diabetic retinopathy, is considered to be important as one of the retinal diseases in patients with diabetes mellitus. Diabetic maculopathy is classified into macular edema, ischemic maculopathy, retinal pigment epitheliopathy and macular traction. The object of diabetic retinopathy therapy is to prevent blindness (loss of visual acuity), while the object of diabetic maculopathy therapy is to prevent and ameliorate deterioration of visual acuity. Macula lutea are significantly different in form from retinas so as to attain high central visual acuity (sharpest and high visual acuity), and have a special structure (absent from an inner plexiform layer and an inner nuclear layer) with extremely fewer tissues other than visual cells. Accordingly, the clinically problematic deterioration of visual acuity is due to maculopathy. A development of photocoagulation and vitrectomy made it possible to almost prevent blindness attributable to retinopathy, but is not satisfactory for maculopathy, so a therapy that is different from retinopathy therapy is needed for maculopathy. This is also important in light of the treatment of many patients having maculopathy only without having retinopathy. Especially, a recent increase in pan-photocoagulation for diabetic retinopathy is estimated to worsen macular edema in diabetic maculopathy, to cause further deterioration of visual acuity. Accordingly, the main point of therapy is shifting toward improvement of quality of life (QOL) of patients by maintaining and improving visual acuity.
Macular edema caused by breakage of a blood-retinal barrier in a retinal vascular endothelial cell or a retinal pigment epithelial cell accounts for about 90% of maculopathy and is a major cause for deterioration of visual acuity in maculopathy. This deterioration of visual acuity does not lead to blindness, but causes extreme deterioration of visual acuity referred to as social blindness making usual living difficult. On one hand, the average life span increases due to the advancement of medical technology, and thus, such a deterioration of visual acuity is a serious problem that cannot be neglected in consideration of QOL. Major therapy conducted for preventing or ameliorating deterioration of visual acuity includes photocoagulation, vitrectomy and chemotherapy. Under the present circumstances, photocoagulation and vitrectomy are examined for their effectiveness in clinical studies, and the effectiveness and safety for macular edema have still not been established. There are cases where complications of neovascular glaucoma and worsening edema occur, and thus, there is an earnest desire for the advent of an effective and safe chemotherapy. In the present chemotherapy, steroids and carbonate dehydratase inhibitors with anti-inflammatory action as major efficacy are used in symptomatic therapy, but their effectiveness is not established and their administration over a long period of time leads to the occurrence of side effects, and thus, the continuous use thereof in chronic diseases such as diabetes mellitus is not desirable under the present circumstance.
(2S,4S)-6-Fluoro-2′,5′-dioxospiro[chroman-4,4′-imidazolidine]-2-carboxamide (hereinafter, referred to as SNK-860) found by the present applicant was developed as a compound which has a strong inhibitory activity on aldose reductase and is highly safe even in administration for a long time, and clinical test thereof as a therapeutic agent for diabetic neuropathy is advancing worldwide at present.
With respect to hydantoin derivatives including SNK-860, the use thereof for diabetic neuropathy is described in JP-A 61-200991 (1986), the use thereof for diseases in circulatory organs in JP-A 04-173791 (1992), the use thereof for various diseases accompanying aging in JP-A 06-135968 (1994), the use thereof for simple diabetic retinopathy in JP-A 07.242547 (1995), and the use thereof for diabetic keratopathy in JP-A 08-231549 (1996). However, the effectiveness of the hydantoin derivatives for diabetic maculopathy has not been reported.
As described above, establishing an effective and highly safe therapy for treating diabetic maculopathy is strongly desired in the medical field. Under the present circumstances, the advent of a highly safe chemotherapy enabling administration over a long time period is strongly desired because of the safety problems associated with treatment by ophthalmologic operation. However, heretofore, there has been no model for evaluating experimental diabetic maculopathy, which is important for the development of such therapeutic agents, and the establishment of an experimental model for development of pharmaceutical preparations is an urgent task.